Review on Recent and Novel Approaches to Colon Targeted...

Human Journals

Review Article

April 2015 Vol.:3, Issue:1

© All rights are reserved by Nalanda T. Rangari et al.

Review on Recent and Novel Approaches to Colon Targeted Drug Delivery Systems

www.ijppr.humanjournals.com

Keywords: Colon targeted drug delivery system, Prodrug, PH

and time dependent systems and microbial triggered systems

ABSTRACT

This article focuses on the potential opportunities and

challenges available in new area of colon targeted drug

delivery system. Colon is a site where both local and systemic

delivery of drugs can take place and oral administration of

different dosage forms is the most common form of

administration due to greater patient compliance and

flexibility. Colon targeted drug delivery system is used for the

treatment of various diseases related to colon like

inflammatory bowel disease, Crohn’s disease, colon cancer,

etc. Colonic drug delivery has gained importance not just for

the delivery of the drugs in the treatment of local diseases

associated with it but also for the systemic delivery of

proteins, therapeutic peptides, anti-asthmatic drugs,

antihypertensive drugs and anti-diabetic agents. In this review

the various concepts and approaches including prodrug, PH

and time dependent systems and microbial triggered systems

used in the development of colon specific drug delivery are

discussed. Review also focuses on the novel approaches

namely pressure controlled colonic delivery, osmotic

controlled drug delivery and CODESTM.

Nalanda T. Rangari1*

, Prashant K. Puranik2

1Swami Ramanand Teerth Marathwada University,

Nanded, Maharashtra, India 2Department of

Pharmaceutical Sciences RTM Nagpur University,

Maharashtra, India.

Submission: 8 April 2015

Accepted: 14 April 2015

Published: 25 April 2015


Citation: Nalanda T. Rangari et al. Ijppr.Human, 2015; Vol. 3 (1): 167-186.

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INTRODUCTION

Colon specific drug delivery has gained a more importance in delivery of the drug in

colonic region by use of various drugs to treat the both local and systemic diseases.

Local diseases include Crohn’s disease, ulcerative colitis, and colorectal cancer and

other serious disorders like nocturnal asthma, hypertension, arthritis and angina can

also be cured by these techniques. Colonic delivery is a good candidature for delivery

of proteins peptides and vaccines where the enzymatic degradation and the hydrolysis

of proteins can be minimized and increases the systemic bioavailability. During the past

decades research is going on to develop the methods to target the drug to the specific

region. The goal of targeted drug delivery is to deliver the drug to the specific organ.

Drug delivery to the colon is beneficial not only for the oral delivery of proteins and

peptide drugs (degraded by digestive enzymes of stomach and small intestine) but also

for the delivery of low molecular weight compounds used to treat diseases associated

with the colon or large intestine.

Table No. 01: Colonic diseases, its sites and active drug components

Targeted

Site Diseases Drug

Local Colorectal cancer, Cystic fibrosis, Chronic

pancreatitis, Pancreatactomy

5- fluorouracil, Digestive

enzymes

Systemic

Oral delivery of vaccines, To prevent gastric

irritation, To prevent first pass metabolism of

orally administered drugs Oral delivery of

peptides

Typhoid, NSAIDS, Steroids

Insulin

Topical

Inflammatory bowel diseases (Crohn’s disease,

Ulcerative colitis), Irritable bowel

Diseases, Amoebiasis

Hydrocortisone, Prednisolone,

Sulfasalazine, Mesalazine,

Mercaptopurine, Metronidazole,

Tinidazole, mebendazole



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Anatomy and Physiology of Colon

Fig. No. 01 Anatomy of colon

The GIT measures about 5 meters long. The different parts of GIT are divided into upper

and lower gastrointestinal tract. The upper GIT includes oesophagus, stomach, and

duodenum. The lower GIT includes small intestine and large intestine. The small

intestine measures an average of about 6.9 meters to 7.1 meters. It includes duodenum,

jejunum and ileum. The main function of small intestine is the absorption of nutrients

and minerals from food. The retention time of small intestine is 3-5 hr. The large

intestine extending from the ileocecal junction to the anus is divided in to three main

parts i.e. colon, the rectum and anal canal. The entire colon is about 5 feet (150 cm) long,

and is divided in to five major segments. Peritoneal folds called as mesentery which is

supported by ascending and descending colon. The right colon consists of the cecum,

ascending colon, hepatic flexure and the right half of the transverse colon. The left colon

contain the left half of the transverse colon, descending colon, splenic flexure and

sigmoid. The rectum is the last anatomic.

The colon is having high water absorption capacity, the colonic contents are considerably

viscous and their mixing is not efficient, thus availability of most drugs to the absorptive

membrane is low. The human colon has over 400 distinct species of bacteria as resident flora, a

possible population of up to 1010 bacteria per gram of colonic contents. The major function of

the colon is the creation of suitable environment for the growth of colonic microorganisms,



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storage reservoir of faecal contents, expulsion of the contents of the colon at an appropriate time

and absorption of potassium and water from the lumen. The absorptive which more than 90% of

the fluid is absorbed. Among the reactions carried out by these gut flora capacity is very high,

each about 2000 ml of fluid enters the colon through the ileocecal valve are azoreduction and

enzymatic cleavage i.e. glycosides. These metabolic processes may be responsible for the

metabolism of many drugs and may also be applied to colon targeted delivery of peptide based

macromolecules such as insulin by oral administration.

Need to target a drug in colonic region:

The drug targeted to colon will ensure following points,

Direct treatment at the disease site, lower dosing and fewer systemic side effects.

Allow oral administration of peptide and protein drugs.

Colon-specific formulation could also be used to prolong the drug delivery.

Both local and systemic drug delivery could be achieved.

Topical treatment of inflammatory bowel disease, e.g. ulcerative colitis or Crohn’s disease.

Such inflammatory conditions are usually treated with glucocorticoids and sulphasalazine

(targeted).

Serious diseases of the colon, e.g. colorectal cancer, might also be capable of being treated

more effectively if drugs were targeted to the colon.

Colonic delivery are also suitable for delivery of drugs which are polar and/or susceptible to

chemical and enzymatic degradation in the upper GI tract, highly affected by hepatic

metabolism, in particular, therapeutic proteins and peptides.

General considerations for designing of colon specific formulations:

To achieve a desired therapeutic action of dosage form, it is necessary to design a suitable

formulation with suitable qualities. In general, delayed release dosage forms are designed to

provide a burst release or a sustained/ prolonged release once they reach colon.

Various included factors are:

• Pathology and pattern of diseases, especially the affected parts of lower GIT or, Physiology

and physiological composition of the healthy colon if the formulation is not intended for



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localized treatment.

• Physicochemical properties and biopharmaceutical properties of the drug such as solubility,

stability and permeability at the intended site of delivery, and the desired release profile of the

active ingredient.

Formulation of drugs for colon specific delivery requires careful consideration of dissolution of

and/or release rate in the colon fluids. Due to the presence of less fluid content in large intestine

than in small intestine the dissolution and release rate from the formulations decreases. The poor

dissolution and release rate may in turn lead to lower systemic availability of drugs. These issues

could be more problematic when the drug candidate is poorly water soluble and/or require higher

doses for therapy. Consequently, such drugs need to be delivered in pre-solubilised form, or

formulation should be targeted for proximal colon, which has more fluid than in the distal colon.

Aside from drug solubility, the stability of the drug in the colonic environment is a further factor

that warrants attention. The drug could bind in a nonspecific manner to dietary residues,

intestinal secretions, mucus or general faecal matter, thereby reducing the concentration of free

drug. Moreover, the resident micro-flora could also affect colonic performance via degradation

of the drug.

Factors affecting colon targeting:

Several factors will affect colon targeting which generally include physiological factors and

pharmaceutical factors.

Physiological factors:

It generally includes Gastric emptying, pH of colon and Colonic micro flora and enzymes.

Gastric emptying:

Drug targeting to the colon upon oral administration depends mainly on gastric emptying and

bowel transit time. Upon reaching the colon the transit time of dosage form depends on the

size of the particles. Smaller particles have more transit time compared to larger particles.

Diarrhoea patients have shorter transit time whereas constipation patients have longer transit

times.



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Table No. 02: Measurements of Parts of GIT and its transit time.

Measurements (Length)

Small Intestine Large Intestine Rectum Anal Colon

Total length 03 meter Total length 1.5 meter 20cm 03cm

-Duodenum: 25cm -Cecum:0 6 cm

GI Organs -Jejunum: 01m Colon:

-Ileum: 02m -Ascending colon: 20-25cm

-Transverse colon: 10-15cm

-Descending colon: 40-

45cm

-Sigmoid portion: 35-40cm

Transit Fasted state Fed state Small Colon transit

through intestine

transit

Time 10 min to 02 hrs Greater than 02 hrs 03 to 04 hrs 20 to 35 hrs

pH of colon:

The pH of GIT varies between different individuals. The food intakes, diseased state etc.

Influences the pH of the GIT. This change in the pH in different parts of GIT is the basis for

the development of colon targeted drug delivery systems. Coating with different polymers is

done to target the drug site.

Table No. 03: pH of different parts of GIT

Parts of GIT pH

Stomach Fasted state: 1.5-2

Fed State: 2-6

Small Intestine 6.6-7.5

Colon Ascending colon: 6.4

Transverse colon: 6.6

Descending colon: 07



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Colonic micro flora and enzymes:

The GIT contains a variety of microorganisms that produces many enzymes need for

metabolism. Growth of this micro flora is controlled by the GIT contents and peristaltic

movements. The enzymes released by different microorganisms E. coli, Clostridia, Lactobacilli,

Eubacteria, Streptococci are responsible for the various metabolic reactions that take place in the

GIT.

Table No. 04: Different micro flora, enzymes and its metabolic reactions

Micro flora Enzymes Metabolic reaction

E. coli,

Bacteroids Nitroreductase Reduces compounds aromatic & heterocyclic nitro

Clostridia,

Lactobacilli Hydrogenase Reduces carbonyl groups & aliphatic double bonds

Clostridia,

Eubacteria Glucosidase Cleavage of glycosidase of alcohols & phenols

Eubacteria,

Clostridia,

Streptococci Sulfatase Cleavage of Osulphates & sulfamates

Pharmaceutical Factors:

Drug candidates:

Due to high retention time of colon, colon causes an increase in the absorption of poorly

absorbed agents like peptides, etc. drugs used for treatment of inflammatory bowel diseases, etc.

are suitable for colon targeted drug delivery system.

Drug carriers:

The selection of carrier for CDDS depends on the nature of the drug, disease for which the drug

is used. The various physicochemical factors of drug that effect the carrier selection includes

chemical nature, stability, partition coefficient, functional groups of drug molecule, etc.



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Polymers Used in Colon Targeting:

Polymer contains a large number of structural unit joined by same type linkage, form into a chain

like structure. These are nowadays used in formulating various pharmaceutical products.

Naturally found polymer, which include gummy exudates, proteins, enzymes, muscle fibre,

polysaccharides. In olden days natural polymers are widely used in pharmacy but a variety of

synthetic polymer are used nowadays for pharmaceutical and cosmetic development, using these

polymer many therapeutic system of body namely controlled drug delivery systems, are

achieved.

Natural polymer:

Guar gum, Pectin, Cyclodextrin, Dextran, Amylase, Chitosan, Chondrotin sulphate, Locust

bean gum.

Synthetic polymer:

Shellac, Ethyl cellulose, Cellulose acetate phthalate, Hydroxy propyl methyl cellulose,

Eudragit, Polyvinyl acetate phthalate.

Approaches for Site Specific Drug Delivery to Colon:

Several approaches are used for site-specific drug delivery for colon specific drug delivery

system which include the following,

Primary approaches for colon targeted drug delivery system:

1. pH sensitive polymer coated drug delivery system.

2. Time controlled (delayed) release drug delivery system

3. Microbial triggered drug delivery

i. Prodrug approach

ii. Polysaccharide based system

4. New approaches for colon targeted drug delivery

i. Pressure controlled drug delivery system (PCDDS)

ii. CODE (combination of pH dependent and microbial triggered CDDS)

iii. Osmotic controlled colon drug delivery system

iv. Pulsatile colon targeted drug delivery: Pulsincap system and Port system



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v. Azo hydrogel

vi. Multiparticulate system based drug delivery

pH sensitive polymer coated drug delivery system:

In the stomach, pH ranges between 1 and 2 during fasting but increases after eating. The pH is

about 6.5 in the proximal small intestine and about 7.5 in the distal small intestine. From the

ileum to the colon, pH declines significantly. It is about 6.4 in the cecum. However, pH values as

low as 5.7 have been measured in the ascending colon in healthy volunteers. The pH in the

transverse colon is 6.6 and 7.0 in the descending colon. Use of pH dependent polymers is based

on these differences in pH levels. The polymers described as pH dependent in colon specific

drug delivery are insoluble at low pH levels but become increasingly soluble as pH rises.

Although a pH dependent polymer can protect a formulation in the stomach and proximal small

intestine, it may start to dissolve in the lower small intestine and the site-specificity of

formulations can be poor. The decline in pH from the end of the small intestine to the colon can

also result in problems, lengthy lag times at the ileocecal junction or rapid transit through the

ascending colon which can also result in poor site-specificity of enteric-coated single-unit

formulations. Most commonly used pH dependent coating polymers are methacrylic acid

copolymers, commonly known as Eudragit S, more specifically Eudragit L and S. Colon targeted

drug delivery systems based on methacrylic resins has described for insulin, prednisolone,

quinolones, salsalazine, cyclosporine, beclomethasone dipropionate and naproxen. Dissolution

studies performed on the mesalazine tablets further confirmed that the release profiles of the drug

could be manipulated by changing the Eudragit L100-55 and Eudragit S100 ratios within the pH

range of 5.5 to 7.0 in which the individual polymers are soluble respectively, and a coating

formulation consisting of a combination of the two copolymers can overcome the issue of high

GI pH variability among individuals.

Fig. No. 02: Release pattern of a multilayer coated system at different pH conditions in GIT



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Time controlled (delayed) release drug delivery system:

Time controlled release system such as sustained or delayed release dosage forms are also very

promising. The transit time varies in different parts of gastrointestinal tract. This transit time is

responsible for the delayed release of drug. The main drawbacks of this delivery system are that

the transit time varies from one person to other and amount of food intake. However due to

potentially large variation of gastric emptying time of dosage forms in humans, in this approach

colon arrival time of dosage forms can not accurately predicted, resulting in poor colonical

availability. The dosage forms may also applicable as colon targeting dosage forms by

prolonging the lag time of about 5.5 hours (range 5 to 6 hours). Disadvantages of this system are-

(i) Gastric emptying time varies markedly between subjects or in a manner dependent on type

and amount of food intake.(ii) Gastrointestinal movement, especially peristalsis or contraction in

the stomach would result in change in gastrointestinal transit of the drug. (iii) Accelerated transit

through different regions of the colon has been observed in patients with the IBD, the carcinoid

syndrome and diarrhea and the ulcerative colitis.

Microbial triggered drug delivery:

These systems are based on the exploitation of the specific enzymatic activity of the microflora

(enterobacteria) present in the colon. The colonic bacteria are predominately anaerobic in nature

and secrete enzymes that are capable of metabolizing substrates such as carbohydrates and

proteins that escape the digestion in the upper GI tract. The enzymes present in the colon are: 1.

Reducing enzymes: Nitroreductase, Azoreductase, N-oxide reductase, sulfoxide reductase,

Hydrogenase etc., 2. Hydrolytic enzymes: Esterases, Amidases, Glycosidases, Glucuronidase,

sulfatase etc. The vast microflora fulfils its energy needs by fermenting various types of

substrates that have been left undigested in the small intestine, e.g. di- and tri-saccharides,

polysaccharides etc. For this fermentation, the microflora produces a vast number of enzymes

like glucoronidase, xylosidase, arabinosidase, galactosidase, nitroreductase, azareducatase,

deaminase, and urea dehydroxylase. Because of the presence of the biodegradable enzymes only

in the colon, the use of biodegradable polymers for colon-specific drug delivery seems to be a

more site-specific approach as compared to other approaches. These polymers shield the drug

from the environments of stomach and small intestine, and are able to deliver the drug to the

colon. On reaching the colon, they undergo assimilation by micro-organism, or degradation by



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enzyme or break down of the polymer back bone leading to a subsequent reduction in their

molecular weight and thereby loss of mechanical strength. They are then unable to hold the drug

entity any longer.

Prodrug approach:

Classical prodrugs design often represents a non-specific chemical approach to mask unwanted

drug properties such as low bioavailability, less site specific, and chemical instability. On the

other hand, targeted prodrug design represents a new strategy for directed and efficient drug

delivery. Particularly, prodrugs targeting to a specific enzyme or a specific membrane

transporter, or both, have potential drug delivery system especially for cancer chemotherapy.

Prodrug is the main approach of microbial triggered drug delivery system in which the drug

release from the formulation is triggered by the microflora present in the gut. Prodrug is the

inactive form of an active parent drug that undergoes enzymatic transformation to release the

active drug. The produrgs are prepared by linking the active drug with hydrophobic moieties like

amino acids, glucoronic acids, glucose, galactose, cellulose, etc.

These prodrug molecules get hydrolysed in the presence of the enzymes released by the

microflora or a specific membrane transporter, or both, have potential drug delivery system

especially for cancer chemotherapy.

Fig. No. 03. Prodrug approach

Targeting specific enzymes:

Glycoside derivatives are hydrophilic and are poorly absorbed from small intestine, but once

they reach colon, they can be effectively liberated by bacterial glycosidases to release the free

drug and facilitates the absorption by the colonic mucosa. Glycosidic prodrug, dexamethasone



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glucoside appeared to be better candidate, about 60% of the prodrug reach caecum as a free

steroids, while parent drug were absorbed in small intestine.

Targeting specific membrane transporters:

When free steroids were administered orally, they were almost absorbed in the small intestine

and less than 1% of the oral dose reached the colon. Nakamura et al. studied the conjugation of

drug molecule to the polar amino acids and prepared prodrugs for colon drug delivery. Proteins

and their basic units, i.e. the amino acids, have polar groups like -NH2 and - COOH. These polar

groups are hydrophilic and reduce the membrane permeability of amino acids and proteins.

Various non-essential amino acids such as glycine, tyrosine, methionine, and glutamic acid were

conjugated to salicylic acid. The conjugate showed minimal absorption and degradation in the

upper GI tract and showed more enzymatic specificity for hydrolysis by colonic enzymes.

Glucuronide and sulphate conjugation is the major mechanism for the inactivation and

preparation for clearance of many drugs. Bacteria of the lower GI tract, however, secrete β-

glucuronidase and can deglucuronidate a variety of drugs in the intestine. The azo linkage

exhibits a wide range of thermal, chemical, photochemical and pharmaceutical properties. The

azo compounds are extensively metabolised by the intestinal bacteria, both by intracellular

enzymatic components and extracellular reduction. The use of these azo compounds for colon

targeting has been in the form of hydrogels as a coating material for coating the drug cores, and

as prodrugs. Sulphasalazine, which was used for the treatment of rheumatoid arthritis, was later

known to have potential in the treatment of inflammatory bowel disease (IBD). This compound

has an azo bound between 5- ASA and sulphapyridine.

Polysaccharide based system:

The polysaccharide which is polymer of monosaccharide retains their integrity, because they are

resistant to digestive action of GI enzymes, matrices of polysaccharide are assessed to remain

intact in physiological environment of stomach and small intestine, as they reach colon they are

acted upon bacterial polysaccharidases and results in degradation of the matrices. Family of

natural polysaccharide has appeal to area of drug delivery as it comprised of polymer with large

number of derivitizable groups, with wide range of molecular weight, varying chemical

composition and forms most low toxicity and biodegradability, yet a high stability. Pectin is a

polysaccharide which contain α- 1, 4 Dgalactouronic acid and 1, 2 D-Rhamnose with D-



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galactose & D-arabinose side chains. A novel colonic drug delivery is investigated. In vitro

experiments demonstrated that high methoxy pectin, when applied as compression coat, proved

capable of coat tablet during condition stimulating gastrointestinal environment and was

susceptible to enzymatic attack. In vivo gamma scintigraphic studies confirmed the in vitro

findings the pectin coating tablets indicate that disintegrating in the colonic region, and

illustrated that degradation by microflora, thus necessities in the development of such derivatives

of pectin which is less water soluble, Calcium pectinate, the insoluble salt of pectin was used for

colon targeted drug delivery of Indomethacin. The use of pectinolytic enzymes to stimulate

breakdown in colon showed that pectin/chitosan mixture was susceptible to enzymatic

breakdown and releasing its content. Some studies carried out to access the potential

pectin:chitosan films for colonic delivery found that pectin alone was able to protect the

premature release, but only when a substantially thick coat was provided. Some researcher

reported that pectin HPMC compressed core tablets of 5- ASA for colon delivery, Drug

dissolution/ system erosion/ Degradation studies were carried out in pH 1.2 and 6.4 buffers using

pectinolytic enzymes, system was designed that transit time from the GI tract and arrival time for

colon is 6 h. It was found that pectin alone was not sufficient to protect the core tablets and

HPMC addition was required to control the stability of pectin. The optimum concentration of

20% HPMC was preferred for 6 h that corresponds to 25-30% erosion and after the influence of

the pectinase systems degrades faster and release 5-ASA to the colon.

New approaches for colon targeted drug delivery:

Pressure controlled drug delivery system (PCDDS):

Digestion mainly occurs due to the contractility of the stomach and peristaltic movement of the

intestine. The contractility movement of stomach leads to the digestion or breakdown of larger

particles to smaller ones which are then transferred to intestine. The peristaltic movement of

intestine is responsible for the passage of bolus from one part of GIT to the next part. The

peristaltic movement of ascending colon transfers the bolus to transverse colon called as mass

peristalsis. These peristaltic movements occur in limited number i.e. three to four times a day.

These peristaltic movements of intestine results in an increase in the luminal pressure. This

increase in luminal pressure is the key point in the development of pressure controlled drug

delivery system. The pressure controlled drug delivery system 25 consists of a capsule in which



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the drug is present. These gelatine capsules are coated with water insoluble polymer like ethyl

cellulose on their inner side. The drug is introduced into the capsule along with suppository base.

The thickness of ethyl cellulose coating determines the disintegration capacity of the capsule.

After administration the suppository base dissolves at body temperature. The water from

intestinal contents is absorbed resulting in increased viscosity which leads to an increase in the

pressure in the capsule. The pressure in the capsule expels the drug into the colon. The intestinal

pressure developed varies with the circadian rhythms, state of body, food administration, etc.

CODE (combination of pH dependent and microbial triggered CDDS)

This method is developed to minimize the problems associated with the pH and time dependent

drug delivery systems. In this system the pH sensitive polymers are used along with the

polysaccharides that are degraded only by specific bacteria present in the intestine. This system

consists of a core tablet coated with three layers of polymer coatings. The outer coating is

composed of the polymer Eudragit L. This coating gets dissolved once the tablet passes though

the pyloric and duodenum and exposes the next coating. The next coating is composed of

Eudragit E. This layer allows the release of lactulose present in the inner core. This released

lactulose gets metabolized into short chain fatty acids that lower the surrounding pH where the

Eudragit E layer dissolves. The dissolving of Eudragit E results in the exposure of the drug. The

other polysaccharides that are used along with the drug in the core tablet are mannitol, maltose,

etc. The bacteria present in the colon are responsible for the degradation of polysaccharides that

are released from the core tablet. The degradation of polysaccharides results in organic acids

formation that lowers the pH of the contents surrounding the tablet.

Fig. No. 04. CODE System



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Osmotic controlled colon drug delivery system:

This system 30 consists of osmotic units. The osmotic units are used either singly or as many as

5-6 push pull units that are encapsulated in a hard gelatin capsule. The push pull units are

bilayered with outer enteric impermeable membrane and inner semi permeable membrane. The

internal or central part of the push pull consists of the drug layer and push payer. The

semipermeable membrane which is present next to the drug layer consists of an orifice through

which the drug contents are expelled during the course of time. The capsule body enclosing the

push pull units gets dissolved immediately after administration. During the passage of the push

pull units through the GIT the enteric impermeable membrane prevents the water absorption into

the unit. The coating gets dissolved once it reaches the small intestine due to higher pH (>7).

Water enters the unit through the semi permeable membrane causing the push layer to swell. The

swelling of the push compartment forces the drug into the surrounding environment through the

orifice. These osmotic controlled drug delivery systems deliver the drug at a constant rate for up

to 24hr.

Fig. No. 05: Osmotic controlled colon drug delivery system

Pulsatile colon targeted drug delivery: Pulsincap system and Port system

Pulsincap system:

In this system the formulation is developed in a capsule form. The plug placed in the capsule

controls the release of the drug. Swellable hydrogels are used to seal the drug contents. The

capsule gets swelled when it comes in contact with the dissolution fluid and after a lag time the

plug gets pushed off from the capsule and the drug will be released. Polymers such as different



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grades of hydroxyl propyl methyl cellulose (HPMC), poly methyl methacrylate and polyvinyl

acetate are used as hydrogel plugs. The lag time is controlled by the length and point of

intersection of the plug in the capsule body.

Fig. No. 06: Drug release mechanism of Pulsincap system

Port system:

In this system the capsule body is enclosed in a semipermeable membrane. The capsule body

consists of an insoluble plug consisting of osmotically active agent and drug formulation. When

the capsule comes in contact with the dissolution fluid the semipermeable membrane permits the

fluid flow into the capsule resulting in the development of pressure in the capsule body which

leads to release of drug due to expelling of the plug. The drug is released at regular intervals with

time gap between the successive intervals.

Fig. No. 07: Drug release mechanism of Port system



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Azo hydrogel:

The pH sensitive monomers and azo cross linking agents in the hydrogel produce the colon

specificity. During their passage through the GIT these hydrogels swell as the pH increases. This

swelling of hydrogels cleaves the cross links in the hydrogel network causing the release of drug

entrapped in the hydrogel. These hydrogels are prepared by cross linking polymerization of N-

substituted (meth) acrylamides, N- tert- butyl acrylamide and acrylic acid with 4, 4-di

(methacryloylamino) azobenzene as cross linking agents. The hydrogels are also prepared by

cross linking polymeric precursors, polymer-polymer reaction using same polymeric precursor

with the corresponding copolymer containing side chains terminating in NH2 groups. The

degradation rate of hydrogel is associated with the degree of swelling and inversely proportional

to the cross linking density.

Multiparticulate system based drug delivery:

The various advantages of multiparticulate systems are increased bioavailability, reduced risk of

local irritation, reduced risk of systemic toxicity. The various multiparticulate approaches

include pellets, microparticles, granules and nanoparticles. Multiparticulates systems are

preferred over single unit dosage forms as the multiparticulate systems enable the drug to reach

the colon quickly and retained in colon for long period of time. These systems pass through the

GIT easily due to their smaller size. Multiparticulate systems are dispersed more uniformly in the

GIT resulting in more uniform drug absorption. Nanoparticles, the preparation of nanoparticles is

simple and these are capable of protecting the protein and peptide drugs from the chemical and

enzymatic degradation in GIT resulting in an increase in their stability and absorption of through

the intestinal epithelium. The polymeric nanoparticles are prepared by various techniques like

polymerization, nanoprecipitation, inverse microemulsion. The methods involve the use of

organic solvents, heat and agitation. The drawback of these methods is that the heat, agitation is

harmful to proteins and peptide drugs. Ionic gelation technique is the most widely used method

for proteins and peptide drugs.

Evaluation test of Colon Drug Delivery System

In vitro evaluation

No standardized evaluation technique is available for evaluation of CDDS as an ideal in vitro



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model should possess in vivo conditions of GIT such as pH, volume, stirring, bacteria, enzymes,

enzyme activity and components of food. These conditions are influenced by diet and physical

stress. The in vitro evaluation of colon targeted drug delivery systems includes the in vitro

dissolution study and in vitro enzymatic test.

In vitro dissolution test

The dissolution testing is done using the conventional basket method. The dissolution testing is

done in different buffers to characterize the behaviour of formulations at different pH levels. The

different media that are used for the dissolution testing of colon targeted drug delivery are pH 1.2

to simulate gastric fluid, pH 6.8 to simulate small intestine, pH 7.4 to simulate large intestine.

The colon targeted drug delivery systems are tested for 2hr in 0.1N HCl, 3hr in pH 6.8 phosphate

buffer and finally at pH 7.4 phosphate buffer. Buffers of the above pH are prepared to evaluate

the colon targeted drug delivery systems.

In vitro enzymatic test

There are 2 tests for the in vitro enzymatic test.

The carrier drug system is incubated in fermenter containing suitable medium for bacteria.

The amount of drug released at different time intervals is determined.

Drug release study is performed in buffer medium containing enzymes pectinase, dextranase

or rat or guinea pig or rabbit cecal contents. The amount of drug released in a particular time

is directly proportional to rate of degradation of polymer carrier.

In vivo evaluation

The in vivo evaluation of the CDDS is done in dogs, guinea pigs, rats and pigs as they resemble

the anatomic and physiological conditions, micro flora of human GIT. The distribution of

various enzymes in GIT of rat and rabbit is comparable to that in human.

CONCLUSION

The colonic region of the GIT has become an increasingly important site for drug delivery and

absorption. Colon targeted drug delivery system offers benefits of local and systemic effects. The

main advantage of CDDS is that the colon offers near neutral pH, a long transit time, reduced



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enzymatic activity and increased responsiveness to absorption enhancers. Colon specificity is

more likely to be achieved with systems that utilize natural materials that are degraded by

colonic bacterial enzymes. Considering the sophistication of colon-specific drug delivery

systems, and the uncertainty of current dissolution methods in establishing possible in vitro/in

vivo correlation, challenges remain for pharmaceutical scientists to develop and validate a

dissolution method that incorporates the physiological features of the colon, and yet can be used

routinely in an industry setting for the evaluation of CDDS.

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